دورية أكاديمية
Netrin G1 Promotes Pancreatic Tumorigenesis through Cancer-Associated Fibroblast–Driven Nutritional Support and Immunosuppression
| العنوان: | Netrin G1 Promotes Pancreatic Tumorigenesis through Cancer-Associated Fibroblast–Driven Nutritional Support and Immunosuppression |
|---|---|
| المؤلفون: | Francescone, Ralph, Barbosa Vendramini-Costa, Débora, Franco-Barraza, Janusz, Wagner, Jessica, Muir, Alexander, Lau, Allison N., Gabitova, Linara, Pazina, Tatiana, Gupta, Sapna, Luong, Tiffany, Rollins, Dustin, Malik, Ruchi, Thapa, Roshan J., Restifo, Diana, Zhou, Yan, Cai, Kathy Q., Hensley, Harvey H., Tan, Yinfei, Kruger, Warren D., Devarajan, Karthik, Balachandran, Siddharth, Klein-Szanto, Andres J., Wang, Huamin, El-Deiry, Wafik S., Vander Heiden, Matthew G., Peri, Suraj, Campbell, Kerry S., Astsaturov, Igor, Cukierman, Edna |
| المصدر: | PMC |
| بيانات النشر: | American Association for Cancer Research (AACR) |
| سنة النشر: | 2021 |
| المجموعة: | DSpace@MIT (Massachusetts Institute of Technology) |
| الوصف: | © 2020 American Association for Cancer Research. Pancreatic ductal adenocarcinoma (PDAC) has a poor 5-year survival rate and lacks effective therapeutics. Therefore, it is of paramount importance to identify new targets. Using multiplex data from patient tissue, three-dimensional coculturing in vitro assays, and orthotopic murine models, we identified Netrin G1 (NetG1) as a promoter of PDAC tumorigenesis. We found that NetG1+ cancer-associated fibroblasts (CAF) support PDAC survival, through a NetG1-mediated effect on glutamate/glutamine metabolism. Also, NetG1+ CAFs are intrinsically immunosup-pressive and inhibit natural killer cell–mediated killing of tumor cells. These protumor functions are controlled by a signaling circuit downstream of NetG1, which is comprised of AKT/4E-BP1, p38/FRA1, vesicular glutamate transporter 1, and glutamine synthetase. Finally, blocking NetG1 with a neutral-izing antibody stunts in vivo tumorigenesis, suggesting NetG1 as potential target in PDAC. SIGNIFICANCE: This study demonstrates the feasibility of targeting a fibroblastic protein, NetG1, which can limit PDAC tumorigenesis in vivo by reverting the protumorigenic properties of CAFs. Moreover, inhibition of metabolic proteins in CAFs altered their immunosuppressive capacity, linking metabolism with immunomodulatory function. |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | application/octet-stream |
| اللغة: | English |
| تدمد: | 2159-8274 2159-8290 |
| العلاقة: | http://dx.doi.org/10.1158/2159-8290.cd-20-0775Test; Cancer Discovery; https://hdl.handle.net/1721.1/136086.2Test |
| الإتاحة: | https://doi.org/10.1158/2159-8290.cd-20-0775Test https://hdl.handle.net/1721.1/136086.2Test |
| حقوق: | Creative Commons Attribution-Noncommercial-Share Alike ; http://creativecommons.org/licenses/by-nc-sa/4.0Test/ |
| رقم الانضمام: | edsbas.9624FE19 |
| قاعدة البيانات: | BASE |
| تدمد: | 21598274 21598290 |
|---|